Daniel Blair, PhD, assistant member in the St. Jude Department of Chemical Biology and Therapeutics, and postdoctoral fellow Maowei Hu, PhD, at work in the lab.
(Memphis, Tenn.—December 11, 2024) The development of molecules to study and treat disease is becoming increasingly burdened by the time and specificity required to analyze the vast amounts of data generated by synthesizing large collections of new molecules. Scientists at St. Jude Children’s Research Hospital present a novel solution to this problem, using the fundamental fragmentation patterns of chemical building blocks to barcode reactions from starting materials to products. In doing so, they have removed a key bottleneck in the process of synthesizing and screening small molecules. The work was published today in Nature.
Current analytical methods lag the scale of rapid, high-throughput analysis desired by researchers. Scientists at St. Jude, led by Daniel Blair, PhD, St. Jude Department of Chemical Biology and Therapeutics, set about solving this problem by capitalizing on a general feature residing in most chemical reactions.
“Generality is essential for doing anything quickly. So, we sought to identify general features which would uniformly encode the analysis of small molecules,” explained Blair, corresponding author of the Nature article. “We discovered that the building blocks we use to create small molecules break apart in specific, predictable ways and that these patterns can then be used as universal barcodes to analyze chemical products.”
A fragmentation-first approach to experimental design
Fragmentation is a fundamental property of chemical matter, but this novel application in the realm of chemical synthesis is giving it new meaning. A general rate for analyzing a chemical reaction’s outcome is conventionally around 3 minutes, but as researchers scale up, analyzing additional reactions with more variables, that amount of time becomes impractical. This work by Blair and the team transforms chemical reaction analysis from a slow, highly customized and specialist-driven method to a streamlined approach driven by simple-to-identify fragmentation barcodes and a single analytical readout.
“Because these fragmentation patterns are a fundamental property of chemical matter, they are reliably transposable from starting materials to products. As soon as you recognize that starting materials can define the analysis of the resulting chemical products, you’ve generalized the entire approach,” said first author Maowei Hu, PhD, St. Jude Department of Chemical Biology and Therapeutics.
This fragmentation-first approach to high-throughput experimental design can be applied in many ways because this fundamental property is not disease- or discipline-specific. Future applications may include the development of antibiotics, antifungals, cancer therapeutics, molecular glues and many more types of molecules.
“We’ve not only transformed the speed of chemical reaction analysis but also paved the way for directly utilizing these molecules to understand and combat diseases,” said Blair. “This advance represents a significant milestone in our mission to develop effective therapies swiftly and efficiently. We’ve transformed chemical reaction analysis from minutes to milliseconds, and in doing so, have shifted the bottleneck from making molecules to finding functions.”
Authors and funding
The study’s other authors include Lei Yang, Nathaniel Twarog, Jason Ochoada, Yong Li, Eirinaios Vrettos, Arnaldo X. Torres-Hernandez, James Martinez, Jiya Bhatia, Brandon Young, Jeanine Price, Kevin McGowan, Theresa Nguyen, Zhe Shi, Matthew Anyanwu, Mary Ashley Rimmer, Shea Mercer, Zoran Rankovic, and Anang Shelat, all of St. Jude.
The study was supported by the National Cancer Institute (R25CA23944), the National Institute of General Medical Sciences (GM132061) and ALSAC, the fundraising and awareness organization of St. Jude.
If you are interested in licensing the technology involved in this work (Rapid high throughput analysis of synthetic chemistry products SJ-24-0002) from St. Jude for further development and/or commercial use, find out more about licensing.
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St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress, and follow St. Jude on social media at @stjuderesearch.
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